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A human homologue of the Drosophila eyes absent gene underlies Branchio-Oto-Renal (BOR) syndrome and identifies a novel gene family

Abstract

A candidate gene for Branchio-Oto-Renal (BOR) syndrome was identified at chromosome 8q13.3 by positional cloning and shown to underlie the disease. This gene is a human homologue of the Drosophila eyes absent gene (eya), and was therefore called EYA1. A highly conserved 271-amino acid C-terminal region was also found in the products of two other human genes (EYA2 and EYA3), demonstrating the existence of a novel gene family. The expression pattern of the murine EYA1 orthologue, Eya1, suggests a role in the development of all components of the inner ear, from the emergence of the otic placode. In the developing kidney, the expression pattern is indicative of a role for Eya1 in the metanephric cells surrounding the ‘just-divided’ ureteric branches.

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References

  1. Melnick, M., Bixler, D., Nance, W., Silk, K. & Yune, H. Familial branchio-oto-renal dysplasia: A new addition to the branchial arch syndromes. Clin. Genet. 9, 25–34 (1976).

    Article  CAS  PubMed  Google Scholar 

  2. Heimler, A. & Lieber, E. Branchio-Oto-Renal syndrome: reduced penetrance and variable expressivity in four generations of a large kindred. Am. J. Med. Genet 25, 15–27 (1986).

    Article  CAS  PubMed  Google Scholar 

  3. Greenberg, C.R., Trevenen, C.L. & Evans, J.A. The BOR syndrome and renal agenesis — prenatal diagnosis and further clinical delineation. Prenatal Diag. 8, 103–108 (1988).

    Article  CAS  PubMed  Google Scholar 

  4. Fraser, F.C., Sproule, J.R. & Hatal, F. Frequency of the Branchio-Oto-Renal (BOR) syndrome in children with profond hearing loss. Am. J. Med. Genet. 7, 341–349 (1980).

    Article  CAS  PubMed  Google Scholar 

  5. Chen, A., Francis, M., Ni, L., Cremers, C.W.R.J., Kimberling, W.J . et al. Phenotypic manifestations of branchiootorenal syndrome. Am. J. Med. Genet. 58, 365–370 (1995).

    Article  CAS  PubMed  Google Scholar 

  6. König, R., Fuchs, S. & Dukiet, C. Branchio-Oto-Renal (BOR) syndrome: variable expressivity in a five-generation pedigree. Eur. J. Pediatr. 153, 446–450 (1994).

    Article  PubMed  Google Scholar 

  7. Gimsing, S. & Dyrmose, J. Branchio-Oto-Renal dysplasia in three families. Ann. Otol., Rhinol. & Laryngol. 95, 421–426 (1986).

    Article  CAS  Google Scholar 

  8. Fraser, F.C., Aymé, S., Halal, F. & Sproule, J. Autosomal dominant duplication of the renal collecting system, hearing loss, and external ear anomalies: a new syndrome? Am. J. Med. Genet. 14, 473–478 (1983).

    Article  CAS  PubMed  Google Scholar 

  9. Sulk, K.K. Embryology of the Ear. in Hereditary Hearing Loss and Its Syndromes (eds Gorlin, R.J., Toriello, H.V. & Cohen, M.M.) 22–42 (Oxford University Press, New York, 1995).

  10. Clapp, W.L. & Abrahamson, D.R. Development and Gross Anatomy of the Kidney, in Renal Pathology: With Clinical and Functional Correlations (eds Tisher, C.C. & Brenner, B.M.) 3–59 (Lippincott, Philadelphia, 1994).

  11. Patterson, L.T. & Dressier, G.R. The regulation of kidney development: new insights from an old model. Curr. Opin. Genet. Develop. 4, 696–702 (1994).

    Article  CAS  Google Scholar 

  12. Haan, E.A. et al. Tricho-Rhino-Phalangeal and Branchio-Oto syndromes in a family with an inherited rearrangement of chromosome 8q. Am. J. Med. Genet. 32, 490–494 (1989).

    Article  CAS  PubMed  Google Scholar 

  13. Vincent, C. et al. A proposed new contiguous syndrome on 8q consists of Branchio-Oto-Renal (BOR) syndrome, Duane syndrome, a dominant form of hydrocephalus and trapeze aplasia; implications for the mapping of the BOR gene. Hum. Mol. Genet. 3, 1859–1866 (1994).

    Article  CAS  PubMed  Google Scholar 

  14. Ni, L. et al. Refined localisation of the branchiootorenal syndrome gene by linkage and haplotype analysis. Am. J. Med. Genet. 51, 176–184 (1994).

    Article  CAS  PubMed  Google Scholar 

  15. Gu, J.Z., Wagner, M.J., Haan, E.A. & Wells, D.E. Detection of a megabase deletion in a patient with branchio-oto-renal syndrome (BOR) and tricho-rhino-phalangeal syndrome (TRPS): implications for mapping and cloning the BOR gene. Genomics 31, 201–206 (1996).

    Article  CAS  PubMed  Google Scholar 

  16. Kalatzis, V., Abdelhak, S., Compain, S., Vincent, C. & Petit, C. Characterisation of a translocation-associated deletion defines the candidate region for the gene responsible for branchio-oto-renal syndrome. Genomics 34, 422–425 (1996).

    Article  CAS  PubMed  Google Scholar 

  17. Bonini, N.M., Leiserson, W.M. & Benzer, S. The eyes absent gene: genetic control of cell survival and differentiation in the developing drosophila eye.. Cell. 72, 379–395 (1993).

    Article  CAS  PubMed  Google Scholar 

  18. Kozak, M. Interpreting cDNA sequences: some insights from studies on translation. Mamm. Genome 7, 563–574 (1996).

    Article  CAS  PubMed  Google Scholar 

  19. Beaudet, A.L. & Tsui, L.-C. A suggested nomenclature for designating mutations. Hum. Mutation 2, 245–248 (1993).

    Article  CAS  Google Scholar 

  20. Kyte, J. & Doolittle, R.F. A simple method for displaying the hydropathic character of a protein. J. Mol. Biol. 157, 105–132 (1982).

    Article  CAS  PubMed  Google Scholar 

  21. Jordan, T. et al. The human PAX6 gene is mutated in two patients with aniridia. Nature Genet. 1, 328–332 (1992).

    Article  CAS  PubMed  Google Scholar 

  22. Hanson, I.M. et al. Mutations at the PAX6 locus are found in heterogeneous anterior segment malformations including Peters' anomaly. Nature Genet. 6, 168–173 (1994).

    Article  CAS  PubMed  Google Scholar 

  23. Mirzayans, F., Pearce, W.G., MacDonald, I.M. & Walter, M.A. Mutation of the PAX6 gene in patients with autosomal dominant keratitis. Am. J. Hum. Genet. 57, 539–548 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Vortkamp;, A., Gessler, M. & Grzeschik, K.-H. GLI3 zinc-finger gene interrupted by translocations in Greig syndrome families. Nature 352, 539–540 (1991).

    Article  PubMed  Google Scholar 

  25. Wagner, T. et al. Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-Related Gene SOX9. Cell 79, 1111–1120 (1994).

    Article  CAS  PubMed  Google Scholar 

  26. Belloni, E. et al. Identification of Sonic Hedgehog as a candidate gene responsible for holoprosencephaly. Nature Genet. 14, 353–356 (1996).

    Article  CAS  PubMed  Google Scholar 

  27. Roessler, E. et al. Mutations in the human Sonic Hedgehog gene cause holoprosencephaly. Nature Genet. 14, 357–360 (1996).

    Article  CAS  PubMed  Google Scholar 

  28. Wilkie, A.O.M. The molecular basis of genetic dominance. J. Med. Genet. 31, 89–98 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Van-De-Water, T.R. et al. Growth factors and development of the stato-acoustic system, in Development of auditory and vestibular systems 2 (ed. Romand, R.) 1–32 (Elsevier, Amsterdam, 1992).

  30. Lufkin, T., Dierich, A., LeMeur, M., Mark, M. & Chambon, P. Disruption of the Hox 1.6 homeobox gene results in defects in a region corresponding to its rostral domain of expression. Cell 66, 1105–1119 (1991).

    Article  CAS  PubMed  Google Scholar 

  31. Chisaka, O., Musci, T.S. & Capecchi, M.R. Developmental defects of the ear, cranial nerves and hindbrain resulting from targeted disruption of the mouse homeobox gene Hox-1.6. Nature 355, 516–520 (1992).

    Article  CAS  PubMed  Google Scholar 

  32. Torres, M., Gomez-Pardo, E., Dressier, G.R. & Gruss, P. Pax-2 controls multiple steps of urogenital development. Development 121, 4057–4065 (1995).

    CAS  PubMed  Google Scholar 

  33. Corey, D.P. & Breakefield, X.O. Transcription factors in inner ear development. Proc. Natl. Acad. Sci. USA 91, 433–436 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Dressier, G.R. The genetic control of renal development. Curr. Opin. Nephrol. & Hypertension 4, 253–257 (1995).

    Article  Google Scholar 

  35. Sanyanusin, P. et al. Mutation of the PAX2 gene in a family with optic nerve colobomas, renal anomalies and vesicoureteral reflux. Nature Genet. 9, 358–363 (1995).

    Article  CAS  PubMed  Google Scholar 

  36. Rothenpieler, U.W. & Dressier, G.R. Pax-2 is required for mesenchyme-to-epithelium conversion during kidney development. Development 119, 711–720 (1993).

    CAS  PubMed  Google Scholar 

  37. Plachov, D. et al. Pax8, a murine paired box gene expressed in the developing excretory sustem and thyroid gland. Development 110, 643–651 (1990).

    CAS  PubMed  Google Scholar 

  38. Kreidburg, J.A. et al. WT-1 is required for early kidney development. Cell 74, 679–691 (1993).

    Article  Google Scholar 

  39. Pontoglio, M. et al. Hepatocyte nuclear factorl inactivation results in hepatic dysfunction, phenylketonuria, and renal Fanconi syndrome. Cell 84, 575–585 (1996).

    Article  CAS  PubMed  Google Scholar 

  40. Hatini, V., Huh, S.O., Herzlinger, D., Soares, V.C. & Lai, E. Essential role of stromal mesenchyme in kidney morphogenesis revealed by targeted disruption of Winged Helix transcription factor BF-2. Genes & Dev. 10, 1467–1478 (1996).

    Article  CAS  Google Scholar 

  41. Stark, K., Vainio, S., Vassileva, G. & McMahon, A.P. Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature 372, 679–683 (1994).

    Article  CAS  PubMed  Google Scholar 

  42. Schuchardt, A., D'agati, V., Larsson-Blomberg, L., Costantini, F. & Pachnis, V. Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor Ret. Nature 367, 380–383 (1994).

    Article  CAS  PubMed  Google Scholar 

  43. Mendelsohn, C. et al. Function of the retinoic accid receptors (RARs) during development. Development 120, 2749–2771 (1994).

    CAS  PubMed  Google Scholar 

  44. Hurst, H. Sequences of bZIP Proteins. Protein Profile 2, 107–119 (1995).

    Google Scholar 

  45. Bryden, M.M., Evans, H.E. & Binns, W. Embryology of the Sheep. J Morphol. 138, 187–205 (1972).

    Article  CAS  PubMed  Google Scholar 

  46. Koseki, C., Herzlinger, D. & Al-Awqati, Q. Apoptosis in metanephric development. J. Cell Biol. 119, 1327–1333 (1992).

    Article  CAS  PubMed  Google Scholar 

  47. Banfi, S. et al. Identification and mapping of human cDNAs homologous to Drosophila mutant genes through EST database searching. Nature Genet. 13, 167–174 (1996).

    Article  CAS  PubMed  Google Scholar 

  48. Yamagata, K. et al. Mutations in the hepatocyte nuclear factor-4α gene in maturity-onset diabetes of the young (MODY1). Nature 384, 458–460 (1996).

    Article  CAS  PubMed  Google Scholar 

  49. Spence, S.E. et al. Genetic localization of Hao-1, blind-sterile (bs), and Emv-13 on mouse chromosome 2. Genomics 12, 403–404 (1992).

    Article  CAS  PubMed  Google Scholar 

  50. Uberbacher, E.G. & Mural, R.J. Locating protein-coding regions in human DNA sequences by a multiple sensor-neural network approach. Proc. Natl. Acad. Sci. USA 88, 11261–11265 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Roach, J.C., Boysen, C., Wang, K. & Hood, L. Pairwise end sequencing: a unified approach to genomic mapping and sequencing. Genomics 26, 345–353 (1995).

    Article  CAS  PubMed  Google Scholar 

  52. Devereux, J., Haeberli, P. & Smithies, O. A comprehensive set of sequence analysis programs for the VAX. Nucl. Acids Res. 12, 387–395 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Brendel, V., Bucher, P., Nourbakhsh, I.R., Blaisdell, B.E. & Karlin, S. Methods and algorithms for statistical analysis of protein sequences. Proc. Natl. Acad. Sci. USA 89, 2002–2006 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Fuchs, R. MacPattern: protein pattern searching on the Apple Macintosh. Comput. Appl. Biosci. 7, 105–106 (1991).

    CAS  PubMed  Google Scholar 

  55. Fuchs, R. Predicting protein function: a versatile tool for the Apple Macintosh. Comput. Appl. Biosci. 10, 171–178 (1994).

    CAS  PubMed  Google Scholar 

  56. Weil, D. et al. Defective myosin VIIA gene responsible for Usher syndrome type 1B. Nature 374, 60–61 (1995).

    Article  CAS  PubMed  Google Scholar 

  57. Henrique, D. et al. Expression of a Delta homologue in prospective neurons in the chick. Nature 375, 787–790 (1995).

    Article  CAS  PubMed  Google Scholar 

  58. Schaeren-Wiemers, N. & Gerfin-Moser, A. A single protocol to detect transcripts of various types and expression levels in neural tissue and cultured cells: In situ hybridization using digoxigenin-labelled cRNA probes. Histochemistry 100, 431–440 (1993).

    Article  CAS  PubMed  Google Scholar 

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Abdelhak, S., Kalatzis, V., Heilig, R. et al. A human homologue of the Drosophila eyes absent gene underlies Branchio-Oto-Renal (BOR) syndrome and identifies a novel gene family. Nat Genet 15, 157–164 (1997). https://doi.org/10.1038/ng0297-157

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